Dry powder aerosols of nanoparticulate drugs

ABSTRACT

There invention discloses aqueous dispersions of nanoparticulate aerosol formulations, dry powder nanoparticulate aerosol formulation, propellant-based aerosol formulations, methods of using the formulations in aerosol delivery devices, and methods of making such formulations. The nanoparticles of the aqueous dispersions or dry powder formulations comprise insoluble drug particles having a surface modifier on the surface thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.12/320,431, filed on Jan. 26, 2009, which is a continuation of U.S.patent application Ser. No. 09/190,138, filed on Nov. 12, 1998, now U.S.Pat. No. 7,521,068. The contents of these applications are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention is directed to aerosol formulations ofnanoparticulate drug compositions, and methods of making and using suchaerosol formulations.

BACKGROUND OF THE INVENTION

The route of administration of a drug substance can be critical to itspharmacological effectiveness. Various routes of administration exist,and all have their own advantages and disadvantages. Oral drug deliveryof tablets, capsules, liquids, and the like is the most convenientapproach to drug delivery, but many drug compounds are not amenable tooral administration. For example, modern protein drugs which areunstable in the acidic gastric environment or which are rapidly degradedby proteolytic enzymes in the digestive tract are poor candidates fororal administration. Similarly, poorly soluble compounds which do notdissolve rapidly enough to be orally absorbed are likely to beineffective when given as oral dosage forms. Oral administration canalso be undesirable because drugs which are administered orally aregenerally distributed to all tissues in the body, and not just to theintended site of pharmacological activity. Alternative types of systemicadministration are subcutaneous or intravenous injection. This approachavoids the gastrointestinal tract and therefore can be an effectiveroute for delivery of proteins and peptides. However, these routes ofadministration have a low rate of patient compliance, especially fordrugs such as insulin which must be administered one or more timesdaily. Additional alternative methods of drug delivery have beendeveloped including transdermal, rectal, vaginal, intranasal, andpulmonary delivery.

Nasal drug delivery relies on inhalation of an aerosol through the noseso that active drug substance can reach the nasal mucosa. Drugs intendedfor systemic activity can be absorbed into the bloodstream because thenasal mucosa is highly vascularized. Alternatively, if the drug isintended to act topically, it is delivered directly to the site ofactivity and does not have to distribute throughout the body; hence,relatively low doses may be used. Examples of such drugs aredecongestants, antihistamines, and anti-inflammatory steroids forseasonal allergic rhinitis.

Pulmonary drug delivery relies on inhalation of an aerosol through themouth and throat so that the drug substance can reach the lung. Forsystemically active drugs, it is desirable for the drug particles toreach the alveolar region of the lung, whereas drugs which act on thesmooth muscle of the conducting airways should preferentially deposit inthe bronchiole region. Such drugs can include beta-agonists,anticholinergics, and corticosteroids.

Devices Used for Nasal and Pulmonary Drug Delivery

Drugs intended for intranasal delivery (systemic and local) can beadministered as aqueous solutions or suspensions, as solutions orsuspensions in halogenated hydrocarbon propellants (pressurizedmetered-dose inhalers), or as dry powders. Metered-dose spray pumps foraqueous formulations, pMDIs, and DPIs for nasal delivery, are availablefrom, for example, Valois of America or Pfeiffer of America.

Drugs intended for pulmonary delivery can also be administered asaqueous formulations, as suspensions or solutions in halogenatedhydrocarbon propellants, or as dry powders. Aqueous formulations must beaerosolized by liquid nebulizers employing either hydraulic orultrasonic atomization, propellant-based systems require suitablepressurized metered-dose inhalers (pMDIs), and dry powders require drypowder inhaler devices (DPIs) which are capable of dispersing the drugsubstance effectively. For aqueous and other non-pressurized liquidsystems, a variety of nebulizers (including small volume nebulizers) areavailable to aerosolize the formulations. Compressor-driven nebulizersincorporate jet technology and use compressed air to generate the liquidaerosol. Such devices are commercially available from, for example,Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain MedicalEquipment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.;Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak,Inc. Ultrasonic nebulizers rely on mechanical energy in the form ofvibration of a piezoelectric crystal to generate respirable liquiddroplets and are commercially available from, for example, OmronHeathcare, Inc. and DeVilbiss Health Care, Inc.

A propellant driven inhaler (pMDI) releases a metered dose of medicineupon each actuation. The medicine is formulated as a suspension orsolution of a drug substance in a suitable propellant such as ahalogenated hydrocarbon. pMDIs are described in, for example, Newman, S.P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224(Butterworths, London, England, 1984).

Dry powder inhalers (DPIs), which involve deaggregation andaerosolization of dry powders, normally rely upon a burst of inspiredair that is drawn through the unit to deliver a drug dosage. Suchdevices are described in, for example, U.S. Pat. No. 4,807,814, which isdirected to a pneumatic powder ejector having a suction stage and aninjection stage; SU 628930 (Abstract), describing a hand-held powderdisperser having an axial air flow tube; Fox et al., Powder and BulkEngineering, pages 33-36 (March 1988), describing a venturi eductorhaving an axial air inlet tube upstream of a venturi restriction; EP 347779, describing a hand-held powder disperser having a collapsibleexpansion chamber; and U.S. Pat. No. 5,785,049, directed to dry powderdelivery devices for drugs.

Droplet/Particle Size Determines Deposition Site

In developing a therapeutic aerosol, the aerodynamic size distributionof the inhaled particles is the single most important variable indefining the site of droplet or particle deposition in the patient; inshort, it will determine whether drug targeting succeeds or fails. SeeP. Byron, “Aerosol Formulation, Generation, and Delivery UsingNonmetered Systems,” Respiratory Drug Delivery, 144-151, 144 (CRC Press,1989). Thus, a prerequisite in developing a therapeutic aerosol is apreferential particle size. The deposition of inhaled aerosols involvesdifferent mechanisms for different size particles. D. Swift (1980);Parodi et al., “Airborne Particles and Their Pulmonary Deposition,” inScientific Foundations of Respiratory Medicine, Scaddings et al. (eds.),pp. 545-557 (W.B. Saunders, Philadelphia, 1981); J. Heyder, “Mechanismof Aerosol Particle Deposition,” Chest, 80:820-823 (1981).

Generally, inhaled particles are subject to deposition by one of twomechanisms: impaction, which usually predominates for larger particles,and sedimentation, which is prevalent for smaller particles. Impactionoccurs when the momentum of an inhaled particle is large enough that theparticle does not follow the air stream and encounters a physiologicalsurface. In contrast, sedimentation occurs primarily in the deep lungwhen very small particles which have traveled with the inhaled airstream encounter physiological surfaces as a result of random diffusionwithin the air stream. For intranasally administered drug compoundswhich are inhaled through the nose, it is desirable for the drug toimpact directly on the nasal mucosa; thus, large (ca. 5 to 100 μm)particles or droplets are generally preferred for targeting of nasaldelivery.

Pulmonary drug delivery is accomplished by inhalation of an aerosolthrough the mouth and throat. Particles having aerodynamic diameters ofgreater than about 5 microns generally do not reach the lung; instead,they tend to impact the back of the throat and are swallowed andpossibly orally absorbed. Particles having diameters of about 2 to about5 microns are small enough to reach the upper- to mid-pulmonary region(conducting airways), but are too large to reach the alveoli. Evensmaller particles, i.e., about 0.5 to about 2 microns, are capable ofreaching the alveolar region. Particles having diameters smaller thanabout 0.5 microns can also be deposited in the alveolar region bysedimentation, although very small particles may be exhaled.

Problems with Conventional Aerosol Compositions and Methods

Conventional techniques are extremely inefficient in delivering agentsto the lung for a variety of reasons. Prior to the present invention,attempts to develop respirable aqueous suspensions of poorly solubledrugs have been largely unsuccessful. For example, it has been reportedthat ultrasonic nebulization of a suspension containing fluorescein andlatex drug spheres, representing insoluble drug particles, resulted inonly 1% aerosolization of the particles, while air-jet nebulizationresulted in only a fraction of particles being aerosolized. Susan L.Tiano, “Functionality Testing Used to Rationally Assess Performance of aModel Respiratory Solution or Suspension in a Nebulizer,” DissertationAbstracts International, 56/12-B, pp. 6578 (1995). Another problemencountered with nebulization of liquid formulations prior to thepresent invention was the long (4-20 min) period of time required foradministration of a therapeutic dose. Long administration times arerequired because conventional liquid formulations for nebulization arevery dilute solutions or suspensions of micronized drug substance.Prolonged administration times are undesirable because they lessenpatient compliance and make it difficult to control the doseadministered. Lastly, aerosol formulations of micronized drug are notfeasible for deep lung delivery of insoluble compounds because thedroplets needed to reach the alveolar region (0.5 to 2 microns) are toosmall to accommodate micronized drug crystals, which are typically 2-3microns or more in diameter.

Conventional pMDIs are also inefficient in delivering drug substance tothe lung. In most cases, pMDIs consist of suspensions of micronized drugsubstance in halogenated hydrocarbons such as chlorofluorocarbons (CFCs)or hydrofluoroalkanes (HFAs). Actuation of the pMDI results in deliveryof a metered dose of drug and propellant, both of which exit the deviceat high velocities because of the propellant pressures. The highvelocity and momentum of the drug particles results in a high degree oforopharyngeal impaction as well as loss to the device used to deliverthe agent. These losses lead to variability in therapeutic agent levelsand poor therapeutic control. In addition, oropharyngeal deposition ofdrugs intended for topical administration to the conducting airways(such as corticosteroids) can lead to systemic absorption with resultantundesirable side effects. Additionally, conventional micronization(air-jet milling) of pure drug substance can reduce the drug particlesize to no less than about 2-3 microns. Thus, the micronized materialtypically used in pMDIs is inherently unsuitable for delivery to thealveolar region and is not expected to deposit below the centralbronchiole region of the lung.

Prior to the present invention, delivery of dry powders to the lungtypically used micronized drug substance. In the dry powder form,micronized substances tend to have substantial interparticleelectrostatic attractive forces which prevent the powders from flowingsmoothly and generally make them difficult to disperse. Thus, two keychallenges to pulmonary delivery of dry powders are the ability of thedevice to accurately meter the intended dose and the ability of thedevice to fully disperse the micronized particles. For many devices andformulations, the extent of dispersion is dependent upon the patient'sinspiration rate, which itself may be variable and can lead to avariability in the delivered dose.

Delivery of drugs to the nasal mucosa can also be accomplished withaqueous, propellant-based, or dry powder formulations. However,absorption of poorly soluble drugs can be problematic because ofmucociliary clearance which transports deposited particles from thenasal mucosa to the throat where they are swallowed. Complete clearancegenerally occurs within about 15-20 minutes. Thus, poorly soluble drugswhich do not dissolve within this time frame are unavailable for eitherlocal or systemic activity.

The development of aerosol drug delivery systems has been hampered bythe inherent instability of aerosols, the difficulty of formulating drypowder and aqueous aerosols of water-insoluble drugs, and the difficultyof designing an optimal drug particle size for an aerosol drug deliverysystem. There is a need in the art for aerosols that deliver an optimaldosage of essentially insoluble drugs throughout the respiratory tractor nasal cavity. The present invention satisfies these needs.

SUMMARY OF THE INVENTION

The present invention is directed to aqueous, propellant-based, and drypowder aerosols of nanoparticulate compositions, for pulmonary and nasaldelivery, in which essentially every inhaled particle contains at leastone nanoparticulate drug particle. The drug is highly water-insoluble.Preferably, the nanoparticulate drug has an effective average particlesize of about 1 micron or less. This invention is an improvement of thenanoparticulate aerosol formulations described in pending U.S.application Ser. No. 08/984,216, filed on Oct. 9, 1997, for “AerosolsContaining Nanoparticulate Dispersions,” specifically incorporated byreference. Non-aerosol preparations of submicron sized water-insolubledrugs are described in U.S. Pat. No. 5,145,684, specificallyincorporated herein by reference.

A. Aqueous Aerosol Formulations

The present invention encompasses aqueous formulations containingnanoparticulate drug particles. For aqueous aerosol formulations, thedrug may be present at a concentration of about 0.05 mg/mL up to about600 mg/mL. Such formulations provide effective delivery to appropriateareas of the lung or nasal cavities. In addition, the more concentratedaerosol formulations (i.e., for aqueous aerosol formulations, about 10mg/mL up to about 600 mg/mL) have the additional advantage of enablinglarge quantities of drug substance to be delivered to the lung in a veryshort period of time, e.g., about 1 to about 2 seconds (1 puff) ascompared to the conventional 4-20 min. administration period.

B. Dry Powder Aerosol Formulations

Another embodiment of the invention is directed to dry powder aerosolformulations comprising drug particles for pulmonary and nasaladministration. Dry powders, which can be used in both DPIs and pMDIs,can be made by spray-drying aqueous nanoparticulate drug dispersions.Alternatively, dry powders containing nanoparticulate drug can be madeby freeze-drying nanoparticulate drug dispersions. Combinations ofspray-dried and freeze-dried nanoparticulate drug powders can be used inDPIs and pMDIs. For dry powder aerosol formulations, the drug may bepresent at a concentration of about 0.05 mg/g up to about 990 mg/g. Inaddition, the more concentrated aerosol formulations (i.e., for drypowder aerosol formulations about 10 mg/g up to about 990 mg/g) have theadditional advantage of enabling large quantities of drug substance tobe delivered to the lung in a very short period of time, e.g., about 1to about 2 seconds (1 puff).

1. Spray-Dried Powders Containing Nanoparticulate Drug

Powders comprising nanoparticulate drug can be made by spray-dryingaqueous dispersions of a nanoparticulate drug and a surface modifier toform a dry powder which consists of aggregated drug nanoparticles. Theaggregates can have a size of about 1 to about 2 microns which issuitable for deep lung delivery. The aggregate particle size can beincreased to target alternative delivery sites, such as the upperbronchial region or nasal mucosa by increasing the concentration of drugin the spray-dried dispersion or by increasing the droplet sizegenerated by the spray dryer.

Alternatively, the aqueous dispersion of drug and surface modifier cancontain a dissolved diluent such as lactose or mannitol which, whenspray dried, forms respirable diluent particles, each of which containsat least one embedded drug nanoparticle and surface modifier. Thediluent particles with embedded drug can have a particle size of about 1to about 2 microns, suitable for deep lung delivery. In addition, thediluent particle size can be increased to target alternate deliverysites, such as the upper bronchial region or nasal mucosa by increasingthe concentration of dissolved diluent in the aqueous dispersion priorto spray drying, or by increasing the droplet size generated by thespray dryer.

Spray-dried powders can be used in DPIs or pMDIs, either alone orcombined with freeze-dried nanoparticulate powder. In addition,spray-dried powders containing drug nanoparticles can be reconstitutedand used in either jet or ultrasonic nebulizers to generate aqueousdispersions having respirable droplet sizes, where each droplet containsat least one drug nanoparticle. Concentrated nanoparticulate dispersionsmay also be used in these aspects of the invention.

2. Freeze-Dried Powders Containing Nanoparticulate Drug

Nanoparticulate drug dispersions can also be freeze-dried to obtainpowders suitable for nasal or pulmonary delivery. Such powders maycontain aggregated nanoparticulate drug particles having a surfacemodifier. Such aggregates may have sizes within a respirable range,i.e., about 2 to about 5 microns. Larger aggregate particle sizes can beobtained for targeting alternate delivery sites, such as the nasalmucosa.

Freeze dried powders of the appropriate particle size can also beobtained by freeze drying aqueous dispersions of drug and surfacemodifier, which additionally contain a dissolved diluent such as lactoseor mannitol. In these instances the freeze dried powders consist ofrespirable particles of diluent, each of which contains at least oneembedded drug nanoparticle.

Freeze-dried powders can be used in DPIs or pMDIs, either alone orcombined with spray-dried nanoparticulate powder. In addition,freeze-dried powders containing drug nanoparticles can be reconstitutedand used in either jet or ultrasonic nebulizers to generate aqueousdispersions having respirable droplet sizes, where each droplet containsat least one drug nanoparticle. Concentrated nanoparticulate dispersionsmay also be used in these aspects of the invention.

C. Propellant-Based Formulations

Yet another embodiment of the invention is directed to a process andcomposition for propellant-based systems comprising nanoparticulate drugparticles and a surface modifier. Such formulations may be prepared bywet milling the coarse drug substance and surface modifier in liquidpropellant, either at ambient pressure or under high pressureconditions. Alternatively, dry powders containing drug nanoparticles maybe prepared by spray-drying or freeze-drying aqueous dispersions of drugnanoparticles and the resultant powders dispersed into suitablepropellants for use in conventional pMDIs. Such nanoparticulate pMDIformulations can be used for either nasal or pulmonary delivery. Forpulmonary administration, such formulations afford increased delivery tothe deep lung regions because of the small (i.e., about 1 to about 2microns) particle sizes available from these methods. Concentratedaerosol formulations can also be employed in pMDIs.

D. Methods of Making Aerosol Formulations

The invention also provides methods for making an aerosol ofnanoparticulate compositions. The nanoparticulate dispersions used inmaking aqueous aerosol compositions can be made by wet milling or byprecipitation methods known in the art. Dry powders containing drugnanoparticles can be made by spray drying or freeze-drying aqueousdispersions of drug nanoparticles. The dispersions used in these systemsmay or may not contain dissolved diluent material prior to drying.Additionally, both pressurized and non-pressurized milling operationscan be employed to make nanoparticulate drug compositions in non-aqueoussystems.

In a non-aqueous, non-pressurized milling system, a non-aqueous liquidwhich has a vapor pressure of 1 atm or less at room temperature is usedas a milling medium and may be evaporated to yield dry nanoparticulatedrug and surface modifier. The non-aqueous liquid may be, for example, ahigh-boiling halogenated hydrocarbon. The dry nanoparticulate drugcomposition thus produced may then be mixed with a suitable propellantor propellants and used in a conventional pMDI.

Alternatively, in a pressurized milling operation, a non-aqueous liquidwhich has a vapor pressure >1 atm at room temperature is used as amilling medium for making a nanoparticulate drug and surface modifiercomposition. Such a liquid may be, for example, a halogenatedhydrocarbon propellant which has a low boiling point. The resultantnanoparticulate composition can then be used in a conventional pMDIwithout further modification, or can be blended with other suitablepropellants. Concentrated aerosols may also be made via such methods.

E. Methods of Using Nanoparticulate Aerosol Formulations

In yet another aspect of the invention, there is provided a method oftreating a mammal comprising: (1) forming an aerosol of a dispersion(either aqueous or powder) of nanoparticles, wherein the nanoparticlescomprise an insoluble drug having a surface modifier on the surfacethereof, and (2) administering the aerosol to the pulmonary or nasalcavities of the mammal. Concentrated aerosol formulations may also beused in such methods.

Another embodiment of the invention provides a method of diagnosing amammal comprising: (1) forming an aerosol of a dispersion (eitheraqueous or dry) of nanoparticles, wherein the nanoparticles comprise aninsoluble diagnostic agent having a surface modifier; (2) administeringthe aerosol to the pulmonary or nasal cavities of the mammal; and (3)imaging the diagnostic agent in the pulmonary or nasal system.Concentrated aerosol formulations can also be employed in suchdiagnostic methods.

Both the foregoing general description and the following detaileddescription are exemplary and explanatory and are intended to providefurther explanation of the invention as claimed. Other objects,advantages, and novel features will be readily apparent to those skilledin the art from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Shows an in vitro deposition pattern of a concentratedaerosolized beclomethasone dipropionate dispersion from an ultrasonicnebulizer.

FIG. 2: Shows an in vitro deposition pattern of a concentratedaerosolized beclomethasone dipropionate dispersion from a jet nebulizer.

FIG. 3: Shows the aerodynamic volume distribution diameter of aspray-dried naproxen aerosol (2% (w/w) naproxen).

FIG. 4: Shows a scanning electron micrograph of spray-dried naproxenaerosol particles (aggregated naproxen/polyvinylpyrrolidone (surfacemodifier) nanoparticles, demonstrating the overall uniformity of sizeand the spherical nature of the particles.

FIG. 5: Shows the aerodynamic volume distribution diameter of aspray-dried naproxen aerosol (5% (w/w) naproxen).

FIG. 6: Shows the aerodynamic volume distribution diameter of aspray-dried triamcinolone acetonide (TA) aerosol (10% (w/w) TA).

FIG. 7: Shows two photomicrographs: FIG. 7(A) shows spray-driednanoparticulate budesonide particles, and FIG. 7(B) shows particles ofmicronized budesonide.

FIG. 8: Shows the particle size distribution (by volume) of areconstituted freeze-dried anti-emetic aerosol containing dextrosediluent.

FIG. 9: Shows the particle size distribution of a reconstitutedfreeze-dried anti-emetic aerosol containing mannitol diluent.

FIG. 10: Shows a scanning electron micrograph of nanoparticulate TAmilled in a non-pressurized propellant system.

FIG. 11: FIG. 11(A) shows aqueous suspension of micronized DrugSubstance, and FIG. 11(B) shows colloidal Dispersion of drugnanoparticles.

FIG. 12: FIG. 12(A) shows micronized drug substance not less than 2 μmin diameter, FIG. 12(B) shows respirable aggregates of nanoparticlesless than 2 μm to 100 μm in diameter, and FIG. 12(C) shows respirablediluent particles containing embedded of nanoparticles, less than 2 μmto 100 μm in diameter.

FIG. 13: FIG. 13(A) shows respirable aggregates of nanoparticles mixedwith an inert carrier, and FIG. 13(B) shows respirable diluent particlescontaining embedded nanoparticles mixed with an inert carrier.

DETAILED DESCRIPTION OF THE INVENTION A. Aerosol Formulations

The compositions of the invention are aerosols which contain drugnanoparticles. Aerosols can be defined as colloidal systems consistingof very finely divided liquid droplets or dry particles dispersed in andsurrounded by a gas. Both liquid and dry powder aerosol compositions areencompassed by the invention.

1. Nanoparticulate Drug and Surface Modifier Particle Size

Preferably, the compositions of the invention contain nanoparticleswhich have an effective average particle size of less than about 1000nm, more preferably less than about 400 nm, less than about 300 nm, lessthan about 250 nm, less than about 100 nm, or less than about 50 nm, asmeasured by light-scattering methods. By “an effective average particlesize of less than about 1000 nm” it is meant that at least 50% of thedrug particles have a weight average particle size of less than about1000 nm when measured by light scattering techniques. Preferably, atleast 70% of the drug particles have an average particle size of lessthan about 1000 nm, more preferably at least 90% of the drug particleshave an average particle size of less than about 1000 nm, and even morepreferably at least about 95% of the particles have a weight averageparticle size of less than about 1000 nm.

2. Concentration of Nanoparticulate Drug

For aqueous aerosol formulations, the nanoparticulate agent is presentat a concentration of about 0.05 mg/mL up to about 600 mg/mL. For drypowder aerosol formulations, the nanoparticulate agent is present at aconcentration of about 0.05 mg/g up to about 990 mg/g, depending on thedesired drug dosage. Concentrated nanoparticulate aerosols, defined ascontaining a nanoparticulate drug at a concentration of about 10 mg/mLup to about 600 mg/mL for aqueous aerosol formulations, and about 10mg/g up to about 990 mg/g for dry powder aerosol formulations, arespecifically encompassed by the present invention. Such formulationsprovide effective delivery to appropriate areas of the lung or nasalcavities in short administration times, i.e., less than about 15 secondsas compared to administration times of up to 4 to 20 minutes as found inconventional pulmonary nebulizer therapies.

3. In Vivo Deposition of Inhaled Aerosols

Aerosols intended for delivery to the nasal mucosa are inhaled throughthe nose. For optimal delivery to the nasal cavities, inhaled particlesizes of about 5 to about 100 microns are useful, with particle sizes ofabout 30 to about 60 microns being preferred. For nasal delivery, alarger inhaled particle size is desired to maximize impaction on thenasal mucosa and to minimize or prevent pulmonary deposition of theadministered formulation. Inhaled particles may be defined as liquiddroplets containing dissolved drug, liquid droplets containing suspendeddrug particles (in cases where the drug is insoluble in the suspendingmedium), dry particles of pure drug substance, aggregates of drugnanoparticles, or dry particles of a diluent which contain embedded drugnanoparticles.

For delivery to the upper respiratory region, inhaled particle sizes ofabout 2 to about 10 microns are preferred, more preferred is about 2 toabout 6 microns. Delivery to the upper respiratory region may bedesirable for drugs such as bronchodilators or corticosteroids that areto act locally. This is because drug particles deposited in the upperrespiratory tract can dissolve and act on the smooth muscle of theairway, rather than being absorbed into the bloodstream of the patient.However, the goal for some inhaled drugs is systemic delivery, such asin cases of proteins or peptides which are not amenable to oraladministration. It is preferred that drugs intended for systemicadministration be delivered to the alveolar region of the lung, because99.99% of the available surface area for drug absorption is located inthe peripheral alveoli. Thus, with administration to the alveolarregion, rapid absorption can be realized. For delivery to the deep lung(alveolar) region, inhaled particle sizes of less than about 2 micronsare preferred.

4. Aqueous Aerosols

Aqueous formulations of the present invention consist of colloidaldispersions of water-insoluble nanoparticulate drug in an aqueousvehicle which are aerosolized using air-jet or ultrasonic nebulizers.The advantages of the present invention can best be understood bycomparing the sizes of nanoparticulate and conventional micronized drugparticles with the sizes of liquid droplets produced by conventionalnebulizers. Conventional micronized material is generally about 2 toabout 5 microns or more in diameter and is approximately the same sizeas the liquid droplet size produced by medical nebulizers. In contrast,nanoparticulate drug particles are substantially smaller than thedroplets in such an aerosol. Thus, aerosols containing nanoparticulatedrug particles improve drug delivery efficiency because they contain ahigher number of drug particles per unit dose such that each aerosolizeddroplet contains active drug substance.

Thus, with administration of the same dosages of nanoparticulate andmicronized drug, more lung or nasal cavity surface area is covered bythe aerosol formulation containing nanoparticulate drug.

Another advantage of the present invention is that it permitswater-insoluble drug compounds to be delivered to the deep lung vianebulization of aqueous formulations. Conventional micronized drugsubstance is too large to reach the peripheral lung regardless of thesize of the droplet produced by the nebulizer, but the present inventionpermits nebulizers which generate very small (about 0.5 to about 2microns) aqueous droplets to deliver water-insoluble drugs in the formof nanoparticles to the alveoli. One example of such devices is theCirculaire® (Westmed Corp., Tucson, Ariz.).

Yet another advantage of the present invention is that ultrasonicnebulizers can be used to deliver water-insoluble drugs to the lung.Unlike conventional micronized material, nanoparticulate drug particlesare readily aerosolized and show good in vitro depositioncharacteristics. A specific advantage of the present invention is thatit permits water-insoluble drugs to be aerosolized by ultrasonicnebulizers which require the drug substance to pass through very fineorifices to control the size of the aerosolized droplets. Whileconventional drug material would be expected to occlude the pores,nanoparticulate drug particles are much smaller and can pass through thepores without difficulty.

Another advantage of the present invention is the enhanced rate ofdissolution of water-insoluble drugs. Since dissolution rate is afunction of the total surface area of drug substance to be dissolved,more finely divided drug particles (e.g., nanoparticles) have muchfaster dissolution rates than conventional micronized drug particles.This can result in more rapid absorption of inhaled drugs. For nasallyadministered drugs it can result in more complete absorption of thedose, since with a nanoparticulate drug dose the particles can dissolverapidly and completely before being cleared via the mucociliarymechanism.

5. Dry Powder Aerosol Formulations

The invention is also directed to dry powders which containnanoparticulate compositions for pulmonary or nasal delivery. Thepowders may consist of respirable aggregates of nanoparticulate drugparticles, or of respirable particles of a diluent which contains atleast one embedded drug nanoparticle. Powders containing nanoparticulatedrug particles can be prepared from aqueous dispersions of nanoparticlesby removing the water via spray-drying or lyophilization (freezedrying). Spray-drying is less time consuming and less expensive thanfreeze-drying, and therefore more cost-effective. However, certaindrugs, such as biologicals benefit from lyophilization rather thanspray-drying in making dry powder formulations.

Dry powder aerosol delivery devices must be able to accurately,precisely, and repeatably deliver the intended amount of drug. Moreover,such devices must be able to fully disperse the dry powder intoindividual particles of a respirable size. Conventional micronized drugparticles of 2-3 microns in diameter are often difficult to meter anddisperse in small quantities because of the electrostatic cohesiveforces inherent in such powders. These difficulties can lead to loss ofdrug substance to the delivery device as well as incomplete powderdispersion and sub-optimal delivery to the lung. Many drug compounds,particularly proteins and peptides, are intended for deep lung deliveryand systemic absorption. Since the average particle sizes ofconventionally prepared dry powders are usually in the range of 2-3microns, the fraction of material which actually reaches the alveolarregion may be quite small. Thus, delivery of micronized dry powders tothe lung, especially the alveolar region, is generally very inefficientbecause of the properties of the powders themselves.

The dry powder aerosols which contain nanoparticulate drugs can be madesmaller than comparable micronized drug substance and, therefore, areappropriate for efficient delivery to the deep lung. Moreover,aggregates of nanoparticulate drugs are spherical in geometry and havegood flow properties, thereby aiding in dose metering and deposition ofthe administered composition in the lung or nasal cavities.

Dry nanoparticulate compositions can be used in both DPIs and pMDIs. (Inthis invention, “dry” refers to a composition having less than about 5%water.)

6. Propellant-Based Aerosols

Another embodiment of the invention is directed to a process andcomposition for propellant-based MDIs containing nanoparticulate drugparticles. pMDIs can comprise either discrete nanoparticles of drug andsurface modifier, aggregates of nanoparticles of drug and surfacemodifier, or inactive diluent particles containing embeddednanoparticles. pMDIs can be used for targeting the nasal cavity, theconducting airways of the lung, or the alveoli. Compared to conventionalformulations, the present invention affords increased delivery to thedeep lung regions because the inhaled nanoparticulate drug particles aresmaller than conventional micronized material (<2 μm) and aredistributed over a larger mucosal or alveolar surface area as comparedto micronized drugs.

Nanoparticulate drug pMDIs of the present invention can utilize eitherchlorinated or non-chlorinated propellants. Concentrated nanoparticulateaerosol formulations can also be employed in pMDIs.

B. Methods of Making Aerosol Formulations

The nanoparticulate drug compositions for aerosol administration can bemade by, for example, (1) nebulizing an aqueous dispersion ofnanoparticulate drug, obtained by either grinding or precipitation; (2)aerosolizing a dry powder of aggregates of nanoparticulate drug andsurface modifier (the aerosolized composition may additionally contain adiluent); or (3) aerosolizing a suspension of nanoparticulate drug ordrug aggregates in a non-aqueous propellant. The aggregates ofnanoparticulate drug and surface modifier, which may additionallycontain a diluent, can be made in a non-pressurized or a pressurizednon-aqueous system. Concentrated aerosol formulations may also be madevia such methods.

1. Aqueous Milling to Obtain Nanoparticulate Drug Dispersions

Milling of aqueous drug to obtain nanoparticulate drug is described inthe '684 patent. In sum, drug particles are dispersed in a liquiddispersion medium and mechanical means is applied in the presence ofgrinding media to reduce the particle size of the drug to the desiredeffective average particle size. The particles can be reduced in size inthe presence of one or more surface modifiers. Alternatively, theparticles can be contacted with one or more surface modifiers afterattrition. Other compounds, such as a diluent, can be added to thedrug/surface modifier composition during the size reduction process.Dispersions can be manufactured continuously or in a batch mode.

2. Precipitation to Obtain Nanoparticulate Drug Compositions

Another method of forming the desired nanoparticle dispersion is bymicroprecipitation. This is a method of preparing stable dispersions ofdrugs in the presence of one or more surface modifiers and one or morecolloid stability enhancing surface active agents free of any tracetoxic solvents or solubilized heavy metal impurities. Such a methodcomprises, for example, (1) dissolving the drug in a suitable solventwith mixing; (2) adding the formulation from step (1) with mixing to asolution comprising at least one surface modifier to form a clearsolution; and (3) precipitating the formulation from step (2) withmixing using an appropriate nonsolvent. The method can be followed byremoval of any formed salt, if present, by dialysis or diafiltration andconcentration of the dispersion by conventional means. The resultantnanoparticulate drug dispersion can be utilized in liquid nebulizers orprocessed to form a dry powder for use in a DPI or pMDI.

3. Non-Aqueous Non-Pressurized Milling Systems

In a non-aqueous, non-pressurized milling system, a non-aqueous liquidhaving a vapor pressure of about 1 atm or less at room temperature andin which the drug substance is essentially insoluble is used as a wetmilling medium to make a nanoparticulate drug composition. In such aprocess, a slurry of drug and surface modifier is milled in thenonaqueous medium to generate nanoparticulate drug particles. Examplesof suitable non-aqueous media include ethanol,trichloromonofluoromethane (CFC-11), and dichlorotetrafluoroethane(CFC-114). An advantage of using CFC-11 is that it can be handled atonly marginally cool room temperatures, whereas CFC-114 requires morecontrolled conditions to avoid evaporation. Upon completion of millingthe liquid medium may be removed and recovered under vacuum or heating,resulting in a dry nanoparticulate composition. The dry composition maythen be filled into a suitable container and charged with a finalpropellant. Exemplary final product propellants, which ideally do notcontain chlorinated hydrocarbons, include HFA-134a (tetrafluoroethane)and HFA-227 (heptafluoropropane). While non-chlorinated propellants maybe preferred for environmental reasons, chlorinated propellants may alsobe used in this aspect of the invention.

4. Non-Aqueous Pressurized Milling System

In a non-aqueous, pressurized milling system, a non-aqueous liquidmedium having a vapor pressure significantly greater than 1 atm at roomtemperature is used in the milling process to make nanoparticulate drugcompositions. If the milling medium is a suitable halogenatedhydrocarbon propellant, the resultant dispersion may be filled directlyinto a suitable pMDI container. Alternately, the milling medium can beremoved and recovered under vacuum or heating to yield a drynanoparticulate composition. This composition can then be filled into anappropriate container and charged with a suitable propellant for use ina pMDI.

5. Spray-Dried Powder Aerosol Formulations

Spray drying is a process used to obtain a powder containingnanoparticulate drug particles following particle size reduction of thedrug in a liquid medium. In general, spray-drying is used when theliquid medium has a vapor pressure of less than about 1 atm at roomtemperature. A spray-dryer is a device which allows for liquidevaporation and drug powder collection. A liquid sample, either asolution or suspension, is fed into a spray nozzle. The nozzle generatesdroplets of the sample within a range of about 20 to about 100 μm indiameter which are then transported by a carrier gas into a dryingchamber. The carrier gas temperature is typically between about 80 andabout 200° C. The droplets are subjected to rapid liquid evaporation,leaving behind dry particles which are collected in a special reservoirbeneath a cyclone apparatus.

If the liquid sample consists of an aqueous dispersion of nanoparticlesand surface modifier, the collected product will consist of sphericalaggregates of the nanoparticulate drug particles. If the liquid sampleconsists of an aqueous dispersion of nanoparticles in which an inertdiluent material was dissolved (such as lactose or mannitol), thecollected product will consist of diluent (e.g., lactose or mannitol)particles which contain embedded nanoparticulate drug particles. Thefinal size of the collected product can be controlled and depends on theconcentration of nanoparticulate drug and/or diluent in the liquidsample, as well as the droplet size produced by the spray-dryer nozzle.For deep lung delivery it is desirable for the collected product size tobe less than about 2 μm in diameter; for delivery to the conductingairways it is desirable for the collected product size to be about 2 toabout 6 μm in diameter, and for nasal delivery a collected product sizeof about 5 to about 100 μm is preferred. Collected products may then beused in conventional DPIs for pulmonary or nasal delivery, dispersed inpropellants for use in pMDIs, or the particles may be reconstituted inwater for use in nebulizers.

In some instances it may be desirable to add an inert carrier to thespray-dried material to improve the metering properties of the finalproduct. This may especially be the case when the spray dried powder isvery small (less than about 5 μm) or when the intended dose is extremelysmall, whereby dose metering becomes difficult. In general, such carrierparticles (also known as bulking agents) are too large to be deliveredto the lung and simply impact the mouth and throat and are swallowed.Such carriers typically consist of sugars such as lactose, mannitol, ortrehalose. Other inert materials, including polysaccharides andcellulosics, may also be useful as carriers.

Spray-dried powders containing nanoparticulate drug particles may usedin conventional DPIs, dispersed in propellants for use in pMDIs, orreconstituted in a liquid medium for use with nebulizers.

6. Freeze-Dried Nanoparticulate Compositions

For compounds that are denatured or destabilized by heat, such ascompounds having a low melting point (i.e., about 70 to about 150° C.),or for example, biologics, sublimation is preferred over evaporation toobtain a dry powder nanoparticulate drug composition. This is becausesublimation avoids the high process temperatures associated withspray-drying. In addition, sublimation, also known as freeze-drying orlyophilization, can increase the shelf stability of drug compounds,particularly for biological products. Freeze-dried particles can also bereconstituted and used in nebulizers. Aggregates of freeze-driednanoparticulate drug particles can be blended with either dry powderintermediates or used alone in DPIs and pMDIs for either nasal orpulmonary delivery.

Sublimation involves freezing the product and subjecting the sample tostrong vacuum conditions. This allows for the formed ice to betransformed directly from a solid state to a vapor state. Such a processis highly efficient and, therefore, provides greater yields thanspray-drying. The resultant freeze-dried product contains drug andmodifier(s). The drug is typically present in an aggregated state andcan be used for inhalation alone (either pulmonary or nasal), inconjunction with diluent materials (lactose, mannitol, etc.), in DPIs orpMDIs, or reconstituted for use in a nebulizer.

C. Methods of Using Nanoparticulate Drug Aerosol Formulations

The aerosols of the present invention, both aqueous and dry powder, areparticularly useful in the treatment of respiratory-related illnessessuch as asthma, emphysema, respiratory distress syndrome, chronicbronchitis, cystic fibrosis, chronic obstructive pulmonary disease,organ-transplant rejection, tuberculosis and other infections of thelung, fungal infections, respiratory illness associated with acquiredimmune deficiency syndrome, oncology, and systemic administration of ananti-emetic, analgesic, cardiovascular agent, etc. The formulations andmethod result in improved lung and nasal surface area coverage by theadministered drug.

In addition, the aerosols of the invention, both aqueous and dry powder,can be used in a method for diagnostic imaging. Such a method comprisesadministering to the body of a test subject in need of a diagnosticimage an effective contrast-producing amount of the nanoparticulateaerosol diagnostic image contrast composition. Thereafter, at least aportion of the body containing the administered contrast agent isexposed to x-rays or a magnetic field to produce an x-ray or magneticresonance image pattern corresponding to the presence of the contrastagent. The image pattern can then be visualized.

D. Summary of Advantages of the Compositions and Methods of theInvention

Using the compositions of the invention, essentially water-insolubledrugs can be delivered to the deep lung. This is either not possible orextremely difficult using aerosol formulations of micronizedwater-insoluble drugs. Deep lung delivery is necessary for drugs thatare intended for systemic administration, because deep lung deliveryallows rapid absorption of the drug into the bloodstream via thealveoli, thus enabling rapid onset of action.

The present invention increases the number of drug particles per unitdose and results in distribution of the nanoparticulate drug particlesover a larger physiological surface area as compared to the samequantity of delivered micronized drug. For systemic delivery via thepulmonary route, this approach takes maximum advantage of the extensivesurface area presented in the alveolar region—thus producing morefavorable drug delivery profiles, such as a more complete absorption andrapid onset of action.

Moreover, in contrast to micronized aqueous aerosol dispersions, aqueousdispersions of water-insoluble nanoparticulate drugs can be nebulizedultrasonically. Micronized drug is too large to be delivered efficientlyvia an ultrasonic nebulizer.

Droplet size determines in vivo deposition of a drug, i.e., very smallparticles, about <2 microns, are delivered to the alveoli; largerparticles, about 2 to about 10 microns, are delivered to the bronchioleregion; and for nasal delivery, particles of about 5 to about 100microns are preferred. Thus, the ability to obtain very small drugparticle sizes which can “fit” in a range of droplet sizes allows moreeffective and more efficient (i.e., dose uniformity) targeting to thedesired delivery region. This is not possible using micronized drug, asthe particle size of such drugs is too large to target areas such as thealveolar region of the lung. Moreover, even when micronized drug isincorporated into larger droplet sizes, the resultant aerosolformulation is heterogeneous (i.e., not all droplets contain drug), anddoes not result in such the rapid and efficient drug delivery enabled bythe nanoparticulate aerosol formulations of the invention.

The present invention also enables the aqueous aerosol delivery of highdoses of drug in an extremely short time period, i.e., 1-2 seconds (1puff). This is in contrast to the conventional 4-20 min. administrationperiod observed with pulmonary aerosol formulations of micronized drug.

Furthermore, the dry aerosol nanoparticulate powders of the presentinvention are spherical and can be made smaller than micronizedmaterial, thereby producing aerosol compositions having better flow anddispersion properties, and capable of being delivered to the deep lung.

Finally, the aerosol compositions of the present invention enable rapidnasal delivery. Nasal delivery of such aerosol compositions will beabsorbed more rapidly and completely than micronized aerosolcompositions before being cleared by the mucociliary mechanism.

Drug Particles

The nanoparticles of the invention comprise a therapeutic or diagnosticagent, which in the invention are collectively are referred to as a“drug.” A therapeutic agent can be a pharmaceutical, including biologicssuch as proteins and peptides, and a diagnostic agent is typically acontrast agent, such as an x-ray contrast agent, or any other type ofdiagnostic material. The drug exists as a discrete, crystalline phase.The crystalline phase differs from a non-crystalline or amorphous phasewhich results from precipitation techniques, such as those described inEPO 275,796.

The invention can be practiced with a wide variety of drugs. The drug ispreferably present in an essentially pure form, is poorly soluble, andis dispersible in at least one liquid medium. By “poorly soluble” it ismeant that the drug has a solubility in the liquid dispersion medium ofless than about 10 mg/mL, and preferably of less than about 1 mg/mL.

Suitable drugs include those intended for pulmonary or intranasaldelivery. Pulmonary and intranasal delivery are particularly useful forthe delivery of proteins and polypeptides which are difficult to deliverby other routes of administration. Such pulmonary or intranasal deliveryis effective both for systemic delivery and for localized delivery totreat diseases of the air cavities.

Preferable drug classes include proteins, peptides, bronchodilators,corticosteroids, elastase inhibitors, analgesics, anti-fungals,cystic-fibrosis therapies, asthma therapies, emphysema therapies,respiratory distress syndrome therapies, chronic bronchitis therapies,chronic obstructive pulmonary disease therapies, organ-transplantrejection therapies, therapies for tuberculosis and other infections ofthe lung, fungal infection therapies, and respiratory illness therapiesassociated with acquired immune deficiency syndrome, oncology therapies,systemic administration of anti-emetics, analgesics, cardiovascularagents, etc.

The drug can be selected from a variety of known classes of drugs,including, for example, analgesics, anti-inflammatory agents,anthelmintics, anti-arrhythmic agents, antibiotics (includingpenicillins), anticoagulants, antidepressants, antidiabetic agents,antiepileptics, antihistamines, antihypertensive agents, antimuscarinicagents, antimycobacterial agents, antineoplastic agents,immunosuppressants, antithyroid agents, antiviral agents, anxiolyticsedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptorblocking agents, blood products and substitutes, cardiac inotropicagents, contrast media, corticosteroids, cough suppressants(expectorants and mucolytics), diagnostic agents, diagnostic imagingagents, diuretics, dopaminergics (antiparkinsonian agents),haemostatics, immunological agents, lipid regulating agents, musclerelaxants, parasympathomimetics, parathyroid calcitonin andbiphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones(including steroids), anti-allergic agents, stimulants and anoretics,sympathomimetics, thyroid agents, vasodilators and xanthines.

A description of these classes of drugs and a listing of species withineach class can be found in Martindale, The Extra Pharmacopoeia,Twenty-ninth Edition (The Pharmaceutical Press, London, 1989),specifically incorporated by reference. The drugs are commerciallyavailable and/or can be prepared by techniques known in the art.

Preferred contrast agents are taught in the '684 patent, which isspecifically incorporated by reference. Suitable diagnostic agents arealso disclosed in U.S. Pat. No. 5,260,478; U.S. Pat. No. 5,264,610; U.S.Pat. No. 5,322,679; and U.S. Pat. No. 5,300,739, all specificallyincorporated by reference.

Surface Modifiers

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products, andsurfactants. Preferred surface modifiers include nonionic and ionicsurfactants. Two or more surface modifiers can be used in combination.

Representative examples of surface modifiers include cetyl pyridiniumchloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol,gum acacia, cholesterol, tragacanth, stearic acid, benzalkoniumchloride, calcium stearate, glycerol monostearate, cetostearyl alcohol,cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkylethers (e.g., macrogol ethers such as cetomacrogol 1000),polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fattyacid esters (e.g., the commercially available Tweens® such as e.g.,Tween 20® and Tween 80® (ICI Specialty Chemicals)); polyethylene glycols(e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (Union Carbide)),dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidalsilicon dioxide, phosphates, sodium dodecylsulfate,carboxymethylcellulose calcium, hydroxypropyl cellulose (HPC, HPC-SL,and HPC-L), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulosesodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA),polyvinylpyrrolidone (PVP), 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde (also known as tyloxapol,superione, and triton), poloxamers (e.g., Pluronics F68® and FIN®, whichare block copolymers of ethylene oxide and propylene oxide); poloxamines(e.g., Tetronic 908®, also known as Poloxamine 908®, which is atetrafunctional block copolymer derived from sequential addition ofpropylene oxide and ethylene oxide to ethylenediamine (BASF WyandotteCorporation, Parsippany, N.J.)); a charged phospholipid such asdimyristoyl phophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic1508® (T-1508) (BASF Wyandotte Corporation), dialkylesters of sodiumsulfosuccinic acid (e.g., Aerosol OT®, which is a dioctyl ester ofsodium sulfosuccinic acid (American Cyanamid)); Duponol P®, which is asodium lauryl sulfate (DuPont); Tritons X-200®, which is an alkyl arylpolyether sulfonate (Rohm and Haas); Crodestas F-110®, which is amixture of sucrose stearate and sucrose distearate (Croda Inc.);p-isononylphenoxypoly-(glycidol), also known as Olin-10G® or Surfactant10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40® (Croda, Inc.);and SA9OHCO, which is C₁₈H₃₇CH₂(CON(CH₃)—CH₂(CHOH)₄(CH₂0H)₂ (EastmanKodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside;n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecylβ-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexylβ-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noylβ-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; and thelike. Tyloxapol is a particularly preferred surface modifier for thepulmonary or intranasal delivery of steroids, even more so fornebulization therapies.

Most of these surface modifiers are known pharmaceutical excipients andare described in detail in the Handbook of Pharmaceutical Excipients,published jointly by the American Pharmaceutical Association and ThePharmaceutical Society of Great Britain (The Pharmaceutical Press,1986), specifically incorporated by reference. The surface modifiers arecommercially available and/or can be prepared by techniques known in theart.

Ratios

The relative amount of drug and surface modifier can vary widely and theoptimal amount of the surface modifier can depend upon, for example, theparticular drug and surface modifier selected, the critical micelleconcentration of the surface modifier if it forms micelles, thehydrophilic-lipophilic-balance (HLB) of the surface modifier, themelting point of the surface modifier, the water solubility of thesurface modifier and/or drug, the surface tension of water solutions ofthe surface modifier, etc.

In the present invention, the optimal ratio of drug to surface modifieris about 1% to about 99% drug, more preferably about 30% to about 90%drug.

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.

Example 1

The purpose of this example was to demonstrate the ability to aerosolizea concentrated nanoparticulate dispersion in an ultrasonic nebulizerwhich incorporates a fine mesh screen in its design. An additionalpurpose of this example was to demonstrate that a therapeutic quantityof a concentrated nanoparticulate corticosteroid can be aerosolized in avery short period of time; e.g., two seconds or less.

Two different nanoparticulate dispersions of beclomethasone dipropionate(BDP) (1.25% and 10% BDP) were aerosolized using an ultrasonic nebulizer(Omron NE-U03 MicroAir®). The nebulizer generated droplets on apiezoelectric crystal and extruded them through a screen which containsultrafine laser-drilled holes, producing an aerosol which has a verynarrow particle size distribution in the range of approximately 1-5 μm.The device was connected to an Andersen cascade impactor with a flowrate at 28.3 liters per minute. For each formulation, the nebulizer wasactuated for two seconds using a programmable timer. The actuation timeroughly corresponds to one inhalation cycle with a pMDI. Afteractuation, each stage of the impactor was analyzed for drug depositionby HPLC analysis.

The data indicate that substantial quantities of drug substance werefound on stages 3-6 of the cascade impactor, corresponding toaerodynamic droplet sizes of about 0.7 to 4.7 μm. The total amount ofdrug in the respirable droplet size range for deep lung delivery (i.e.,particles less than about 2 microns; Stages 5, 6, and 7) was 11.72 μgfor the 1.25% BDP (w/w) dispersion and 18.36 μg for the 10% BDP (w/w)dispersion. The total amount of drug in the respirable droplet sizerange for upper pulmonary delivery (i.e. particles about 2 to 5 microns;Stages 2, 3, 4, and 5) was 17.26 μg for the 1.25% BDP dispersion and178.40 μg for the 10% BDP dispersion.

One advantage provided by nanoparticulate formulations is that the drugparticles are small enough to pass through the finer mesh channels ofthe nebulizer. In contrast, conventional micronized drug material wouldbe expected to clog the orifices in the screen. Cascade impactor datafrom an in vitro deposition study of a nanoparticulate BDP dispersionaerosolized by an Omron NE-U03 Ultrasonic Nebulizer are summarized inTable I below:

TABLE I Observed In-Vitro Deposition Pattern of an AerosolizedNanoparticulate BDP Dispersion Deposition Site/ Droplet Size Range 1.25%BDP^(b) 10% BDP^(c) Impactor Area (μm)^(a) (μg Collected) (μg Collected)Stage 0  9.0-10.0 4.76 19.30 Stage 1 5.8-9.0 1.95 37.50 Stage 2 4.7-5.80.75 42.00 Stage 3 3.3-4.7 1.73 79.40 Stage 4 2.1-3.3 5.97 45.20 Stage 51.1-2.1 8.81 11.80 Stage 6 0.7-1.1 2.09 3.59 Stage 7 0.4-0.7 0.82 2.97After Filter <0.4 2.25 18.70 TOTAL 29.13 260.46 Collar N/A 0.00 N/AInduction Port N/A 4.10 22.40 Adapter N/A N/A N/A Tube N/A N/A 10.98^(a)All results based on 2 second actuation with the Omron NE-U03.^(b)Particle Size of concentrate BDP 1.25% (w/w): mean of 171 nm, 90%<234 nm, standard deviation 30 nm ^(c)Particle Size of concentrate BDP10% (w/w): mean of 94 nm, 90% <130 nm, standard deviation 30 nm

The results, which are graphically depicted in FIG. 1, show substantialdeposition of drug at Stages 2, 3, 4, and 5. This corresponds todelivery to conducting airways. Most of the drug substance is found indroplets of about 2 to about 6 which are ideal for delivery to thebronchiole region.

Example 2

The purpose of this example was to demonstrate aerosolization of ananoparticulate dispersion using a using a jet nebulizer (Circulaire®,Westmed, Inc., Tucson, Ariz.), which can produce aqueous droplets in thesize range of 0.5-2.0 μm. Such droplet sizes are suitable for deliveryto the alveolar region of the lung, i.e., deep lung delivery.

A nanoparticulate dispersion of BDP was prepared by wet millingmicronized drug substance in an aqueous tyloxapol surface modifiersolution until a satisfactory particle size distribution had beenobtained. The formulation was evaluated by light scattering methods(Microtrac UPA, Leeds & Northrup) and was found to have a mean particlesize of 139 nm, with 90% of the particles being less than 220 nm (volumestatistics).

The delivery performance of the BDP/surface modifier dispersion in a jetnebulizer was evaluated as follows: Approximately 3.5 ml of theBDP/surface modifier dispersion (2 mg/ml) was added to the nebulizerbowl, and the nebulizer mouthpiece was connected to the throat of acascade impactor apparatus with an airtight seal. The nebulizer andcascade impactor were then operated under suitable pressure and flowconditions for approximately 4 minutes using a 4 seconds on/4 secondsoff cycle. Upon completion of the nebulization, each section of theapparatus was rinsed with acetonitrile and the washings dilutedvolumetrically.

The quantity of drug substance present in each section of the apparatuswas determined by high performance liquid chromatography.

Results

Analysis of the chromatograms showed that relatively little drugsubstance was deposited in the higher regions of the cascade impactorapparatus, while substantial quantities of material appeared on stages5-7, as well as on the exit filter. In Experiment 1, approximately 92%of the emitted dose (ex-device) was contained in droplets <2.1 μm indiameter; in Experiment 2 the value was 86%. The results indicate thatsubstantial quantities of drug substance were found on cascade impactorstages 5, 6, and 7, corresponding to droplet sizes of about 0.43 toabout 2.1 microns. The smallest drug particle size normally accessibleby conventional micronization methods for raw materials is about 2 to 3microns, which is clearly larger than the droplets generated by this jetnebulizer. Detailed results of the cascade impactor study are presentedTable II below, and graphically in FIG. 2.

TABLE II Observed In Vitro Deposition Pattern of a Nanoparticulate BDPSuspension Droplet Size Deposition Site Range (μm) Experiment 1^(a)Experiment 2^(a) Throat 33.13 36.00 Preselector, Stage 0 >9.0  17.6465.27 Stages 1 and 2 4.7-9.0 19.90 80.69 Stage 3 3.3-4.7 8.76 55.59Stage 4 2.1-3.3 2.13 17.90 Stage 5 1.1-2.1 122.41 336.16 Stage 60.65-1.1  354.20 580.20 Stage 7 0.43-0.65 286.42 376.11 filter <0.43297.60 297.15 TOTAL 1142.19 1845.07 ^(a)μg of BDP Collected

In contrast to Example 1, which used an ultrasonic nebulizer (OmronNE-U03 MicroAir®) that generates droplets in the range of 2-6 μm, thisexample used a jet nebulizer that generates droplets in the range of <2μm. The successful deposition of aerosol drug particles at Stages 6 and7 demonstrates the effectiveness of using such compositions for deeplung delivery.

Example 3

The purpose of this example was to demonstrate the preparation of ananoparticulate dry powder for use in a DPI.

40.0% (w/w) naproxen, 4.00% (w/w) PVP K29/30 (a surface modifier), and56.0% (w/w) deionized water were milled with 500 μm SDy-20 polymericmedia for 7.5 hours to achieve a mean particle size of 254 nm, with 90%of the particles having a size of less than 335 nm. The material wasdiluted to 20% (w/w) naproxen and further milled with 50 μm SDy-20 mediafor a period of 6 hours to yield a mean particle size of 155 nm, with90% of the particles having a particle size of less than 212 nm. Thenanoparticulate dispersion was then diluted to 2% (w/w) naproxen withsufficient quantities of Sterile Water for Injection. The suspension wasthen spray-dried using a Yamato GB-22 operating with the followingparameters:

Inlet Temp.: 130° C.

Outlet Temp.: 71-76° C.

Drying Air: 0.37 m³/min.

Atom. Air: 2 M Pa

Pump Speed: ca. 8.4 mL/min.

The resultant nanoparticulate powder possessed a MMAD of 1.67 μm, with90% of the particles having a MMAD of less than 2.43 μm, as determinedby a time-of-flight particle sizing instrument. See FIG. 3, which showsthe volume distribution by the aerodynamic diameter of the spray-driednaproxen aerosol. Thus, all particles fell within the respirable sizerange required for pulmonary deposition. Additionally, greater than 50percent of the particle population fell within the size required forperipheral lung deposition (alveolar, <2 μm).

Interestingly, the spray-dried drug particles also demonstrated aspherical shape, which will improve the flow properties of the powder(as compared to prior micronized spray-dried powder formulations). Theelectron micrograph of FIG. 4 clearly shows the overall uniformity ofsize and the spherical nature of the particles. In addition, theexterior surface of the drug particle, which is composed of thepolymeric stabilizer, may have advantages in limiting moisture uptakeupon storage.

Lastly, to demonstrate that these spray-dried particles are constructedof aggregates of the original nanoparticulate drug, reconstitution in aliquid medium resulted in the return to the original nanoparticulatedispersion, with a mean particle size of 184 nm, and 90% of theparticles having a size of less than 255 nm.

Example 4

The purpose of this example was to further demonstrate the ability toinfluence the aerodynamic size of the spray-dried nanoparticulatecomposition by using a different concentration of nanoparticulate drugdispersion.

The concentration of naproxen and surface modifier (PVP K29/30) was thesame as in Example 5, except that the composition was diluted withSterile Water for Injection to achieve a 5% (w/w) naproxen suspension.The spray-drier used was the Yamato GB-22, with the same operatingparameters used in Example 4.

The resultant powder was composed of nanoparticulate aggregates with aMMAD of 2.91 μm, with 90% of the drug particles having a MMAD of lessthan 4.65 μm. This material is within the desired range for inhaledpulmonary deposition and may be more suitable for central airwaytargeting, i.e., within a range of 2 to 6 μm. See FIG. 5, which showsthe volume distribution by the aerodynamic diameter of the spray-driednaproxen aerosol.

Example 5

The purpose of this example was to produce a spray-dried nanoparticulatepowder or aerosol administration.

20.0% (w/w) triamcinolone acetonide (TA), 2.00% (w/w) HPC-SL (a surfacemodifier), 0.01% (w/w) benzalkonium chloride (BKC), and 76.9% (w/w)deionized water was milled in the presence of 500 μm SDy-20 polymericmedia for approximately one hour. The final drug mean particle size was169 nm, with 90% of the drug particles having a size of less than 259nm. The nanoparticulate drug dispersion was then diluted to 10% (w/w) TAwith a 0.01% BKC solution. The dispersion was then spray-dried using aBuchi B-191 spray-drier at the following settings:

Inlet Temp.: 130° C.

Outlet Temp. 76° C.

Aspirator setting: 90% capacity

Product feed: 18% capacity

The resultant nanoparticulate powder possessed aggregates ofnanoparticulate

TA particles with a MMAD of 5.54 μm, and 90% of the TA particles had aMMAD of less than 9.08 μm via a time-of-flight measuring system. Thus,50 percent of the particles fall within the respirable range for centralairway (bronchiole deposition). See FIG. 6, which shows the volumedistribution by the aerodynamic diameter of the spray-dried TA aerosol.In addition, the TA powder was of spherical shape as compared to thejet-milled drug, thus affording improved flow properties. Lastly, thepowder redisperses in liquid medium to achieve well-dispersednanoparticles of drug at a mean particle size of 182 nm.

Example 6

The purpose of this example was to produce a spray-dried nanoparticulatedrug/surface modifier powder for aerosol administration, wherein thecomposition lacks a diluent. In addition, this example compares thedeposition of the nanoparticulate powder with the deposition of amicronized drug substance in a dry-powder delivery device. 10% (w/w)budesonide, 1.6% (w/w) HPMC (surface modifier), and 88.4% (w/w)deionized water were milled in the presence of 500 μm SDy-20 polymericmedia for 1.5 hours. The resultant mean particle size was 166 nm, with90% of the particles having a size of less than 233 nm. Thenanoparticulate dispersion was then diluted to 0.5% (w/w) budesonidewith deionized water. The dispersion was spray-dried using a YamatoGB-22 spray-dryer operating at the following parameters:

Inlet Temperature: 125° C.

Drying Air: 0.40 m³/minute

Atomizing Air: 0.2 MPa

Outlet Temperature: 60-61° C.

The resultant nanoparticulate aggregates possessed a MMAD of 1.35 μm,with 90% of the particles having a MMAD of less than 2.24 μm, asmeasured by time-of-flight methodology.

A final powder blend was made, composed of 4% (w/w) nanoparticulatebudesonide/surface modifier (3.2% (w/w) drug) and 96% lactose. Themixing was carried out using a Patterson-Kelley V-Blender with Lexanshell. The same procedure was followed for micronized budesonide at 3.4%(w/w) drug (Sicor, Via Terrazano 77, Italy).

Each drug powder—the nanoparticulate and the micronized—was then loadedinto a Clickhaler™ (ML Laboratories plc, England), having a 1.5 mm³dosing chamber. Each unit was evaluated using an Andersen cascadeimpactor operating at approximately 60 liters per minute. Fiveactuations were delivered to the impactor and the unit was thendisassembled and the collection plates analyzed via HPLC. This wasperformed in triplicate. The data as percent of emitted dose from theDPI is shown below in Table III.

TABLE III In vitro Deposition of Nanoparticulate Budesonide vsMicronized Budesonide in a DPI^(a) Aerodynamic Particle Size RangeNanoparticulate Micronized Impactor Region (μm) Budesonide BudesonideStage 0  5.9-10.0 14.1 16.7 Stage 1 4.1-5.9 1.03 5.31 Stage 2 3.2-4.13.09 4.76 Stage 3 2.1-3.2 14.9 7.74 Stage 4 1.4-2.1 26.7 5.73 Stage 50.62-1.4  12.1 3.48 Stage 6 0.35-0.62 2.22 N/D Stage 7 0.15-0.35 0.39N/D After Filter  <0.15 N/D N/D Total Respirable <5.9 60.4 27.0 TotalSystemic <2.1 41.4 9.21 Cone N/A 0.40 0.94 Induction Port N/A 12.7 44.0Adapter N/A 12.4 11.3 ^(a)As percent of emitted dose through device.Cascade Impactor operated at ca. 60 L/min.

The results indicate that the nanoparticulate budesonide powderdelivered 60.4% of the dose to the respirable regions of the impactor,while only 27% of the micronized drug was delivered to the same region.Furthermore, 41.4% of the nanoparticulate aggregates were found in theregion corresponding to alveolar lung deposition, in contrast to only9.21% for the micronized material. Thus, the spray-dried nanoparticulateaggregates were more efficiently aerosolized than the micronized drug.About 450% more in vitro deposition was observed within the systemicregion for the nanoparticulate aggregates as compared to the micronizeddrug blend (measured as percent of delivered dose). Electron micrographsof the nanoparticulate and micronized dry substance formulations areshown in FIG. 7.

Example 7

The purpose of this example was to demonstrate the production offreeze-dried nanoparticulate drug compositions for use in aerosolformulations.

10.0% (w/w) of a novel anti-emetic, 2.00% (w/w) of Poloxamer 188® (asurface modifier), 0.500% (w/w) PVP C-15, and 87.5% (w) of Sterile Waterfor Injection was milled in the presence of 500 μm SDy-20 polymericmedia for a period of 2 hours. A composition having a mean particle sizeof 286 nm, with 90% of the particles having a size of less than 372 nm,was determined via the Horiba LA-910 particle sizer. This material wasthen diluted to 5% (w/w) drug with Sterile Water for Injection andsubjected to 60 minutes milling with 50 μm SDy-20 media. The finalparticle size obtained was 157 nm, with 90% of the drug particles havinga size of less than 267 nm, as determined via the Horiba LA-910. Thisdispersion was then utilized in a series of freeze-drying experimentsbelow.

The freeze-dryer utilized was an FTS Dura-Stop system with operatingparameters as follows:

Product freeze temperature: −30° C. (2 hours hold)

Primary Drying:

1. Shelf temperature set: −25° C. Chamber vacuum: 100 mT Hold time: 2000min. 2. Shelf temp.: −10° C. Chamber vacuum: 100 mT Hold time: 300 min.3. Shelf temp.: 0° C. Chamber vacuum: 100 mT Hold time: 300 min. 4.Shelf temp.: 20° C. Chamber vacuum: 50 mT Hold time: 800 min.

Example 7A

The following freeze-dried material was reconstituted in deionized waterand examined for particle size distribution via the Horiba LA-910particle analyzer: 5.00% (w/w) novel anti-emetic, 5.00% (w/w) dextrose,1.00% (w/w) Poloxamer 188®, 0.250% (w/w) PVP C-15, and 88.8% (w/w)Sterile Water for Injection.

The average particle size of the reconstituted nanoparticulatedispersion was 4.23 μm, with 90% of the particles having an averageparticle size of less than 11.8 μm. The resultant material demonstratesthat aggregates were present in the freeze-dried material havingsuitable particle sizes for pulmonary deposition. See FIG. 8, whichshows the particle size distribution of the freeze-dried anti-emeticaerosol. (For this example, the particle sizes were measured by weight.)

Example 7B

The following freeze-dried material was reconstituted in deionized waterand examined for particle size distribution via the Horiba LA-910particle analyzer: 1.00% (w/w) novel anti-emetic, 5.00% (w/w) mannitol,0.200% (w/w) Poloxamer 188, 0.050% (w/w) PVP C-15, and 93.8% (w/w)Sterile Water for Injection.

The resultant powder when reconstituted demonstrated an average particlesize of 2.77 μm, with 90% of the drug particles having an averageparticle size of less than 7.39 μm. Thus, aggregates of thenanoparticulate anti-emetic have a particle size within an acceptablerange for pulmonary deposition after patient inhalation. See FIG. 9,which shows the particle size distribution of the freeze-driedanti-emetic aerosol. Also, if larger aggregates are generated (beyondabout 5 to about 10 μm), jet-milling may be employed to decrease theparticle size distribution of the system for pulmonary indications.

All of the dry powder inhalation systems can be utilized in either unitdose or multi-dose delivery devices, in either DPIs or pMDIs, and innebulizer systems.

Example 8

The purpose of this prophetic example is to demonstrate the productionof a propellant-based pMDI. This aerosol dosage form for pulmonarydeposition has been the most routinely prescribed for asthmaindications. The system is pressurized by using a propellant, such as aCFC or HFA (hydrofluorinated alkane), which functions as the deliverymedium for a micronized drug. Additionally, a valve lubricant ispresent. These are typically the only components for suspension-basedpMDIs. The micronized drug is jet-milled to the appropriate size forlung deposition (about 3 to about 5 μm).

In contrast, the present invention is directed to the use of eitherdiscrete nanoparticles or aggregates of nanoparticles. For preparationof discrete nanoparticulate drug, a non-aqueous milling medium is used,comprised of a high boiling point propellant. By employing a CFC-11 ortrichloromonofluoromethane milling medium, nanoparticulate drug withsuitable modifier can be made in a non-pressurized milling system. Forexample, the boiling point of CFC-11 is 23.7° C. (according to the MerckIndex). Thus, by maintaining the milling chamber temperature below 23.7°C., the CFC-11 remains intact during the size reduction process withoutdeveloping internal pressure.

After the size reduction process, the propellant can be evaporated andreclaimed in a condenser. The resultant powder of nanoparticulate drugand surface modifier can then be resuspended in non-CFC propellants.Compounds HFA-134a (tetrafluoroethane) and HFA-227 (heptafluoropropane)(Solvay Fluorides, Inc., Greenwich, Conn.; Dupont Fluorochemicals,Wilmington, Del.) are the most widely recognized non-CFC propellants.These can be pressure-filled into canisters containing thenanoparticulate drug and surface modifier.

Example 8A

The purpose of this example was to prepare a nanoparticulate aerosolformulation in a non-aqueous, non-pressurized milling system.

The following material was subjected to milling for 1.5 hrs with SDy-20500 μm polymeric media: 5.00% (w/w) triamcinolone acetonide (TA), 0.500%(w/w) Span 85® (surface modifier), and 94.5% (w/w) CFC-11. The resultantdispersion was then harvested and the propellant evaporated. A scanningelectron microgragh was taken of the resultant powder to inspect forsize reduction of the drug crystals. See FIG. 10. Significant sizereduction of drug particles was observed, and a large population ofsmaller drug crystals was found to be present. This material is ofsufficient size to be respirable for inhaled administration via a pMDIor DPI system.

An exemplary corticosteroid formulation can comprise the following:0.066% (w/w) nanoparticulate TA, 0.034% (w/w) Span 85, and 99.9%HFA-134a. Assuming a product density of 1.21 g/ml and a 50 μl meteringvalve, a theoretical delivery of 40 μg TA is achieved. If necessary,this quantity can be modified to compensate for actuator efficiency.Ideally, the nanoparticulate powder can be dispensed into an appropriatecontainer, followed by pressurized propellant filling, or a bulk slurrycan be prepared and introduced into the final form by cold filling orpressure filling.

Example 9

The purpose of this example was to describe the use of a nanoparticulateaerosol in a propellant system operating at pressurized conditions. Apressurized system allows the processing to progress at ambient roomtemperature.

The milling is conducted using either ball milling with ceramic/glassmedia or high-energy Dyno-milling with modifications to containapproximately 100 psig. The intent is to load the unit with chilledpropellant and seal the sample ports. Thus, if the mill or roller bottleis at room temperature, the propellant will vaporize to maintainequilibrium within the containment system. A balance will be madebetween propellant in a liquid state and in a vapor state. This allowsfor milling in a liquid medium (the propellant) at temperatures abovethe propellant's boiling point.

Exemplary useful non-chlorinated propellants include HFA-134a(tetrafluoroethane), comprising about 50 to about 99.9% of final productweight, milling within pressure at/below 100 psig, and temperaturesat/below 25° C.; and HFA-227 (heptafluoropropane), comprising about 50to about 99.9% of final product weight, milling within pressure at/below53 psig, and temperatures at/below 25° C. In addition, chlorinatedpropellants can be used in this embodiment. Exemplary chlorinatedpropellants include Freon-12 (dichlordifluoromethane), comprising about50 to about 99.9% of milling composition, processed within pressureat/below 85 psig, and temperatures at/below 25° C.; and Freon-114(dichlorotetrafluoroethane), comprising about 50 to about 99.9% ofmilling slurry, processed at pressure at/below 19 psig, and temperaturesat/below 25°.

Example 9A

In this prophetic example, the following compounds can be combined foran exemplary budesonide aerosol composition to be used in a propellantsystem operating at pressurized conditions: 5.00% (w/w) budesonide,0.500% PVP C-15, and 94.5% (w/w) HFA-134a.

The nanoparticulate aerosol composition would be further diluted asnecessary to obtain desired delivery doses.

Example 9B

In this prophetic example, the following compounds can be combined foran exemplary TA aerosol composition to be used in a propellant systemoperating at pressurized conditions: 5.00% (w/w) TA, 0.500% PEG-400, and94.5% (w/w) HFA-227.

The nanoparticulate aerosol composition would be further diluted asnecessary to obtain desired delivery doses.

Example 10

The purpose of this example was to demonstrate the use of powderscomprising spray-dried or freeze-dried nanoparticulate aggregates ordiscrete nanoparticulate particles in propellant systems for inhalation.The MMAD of the nanoparticulate aggregates would be about 0.5 μm toabout 6.0 μm, and the mean particle diameter of the discretenanoparticulate drug particles would be about <1000 nm. This allows foraqueous milling and subsequent water removal. The remaining powder canthen be reconstituted with a propellant, such as those listed above.

The following can be combined for use in a propellant based system forinhalation: 0.704% (w/w) nanoparticulate agent/surface modifier and99.3% (w/w) HFA-227. The resultant nanoparticulate powder is aspray-dried aggregate with a MMAD of 2.0 μm. Based on a theoreticalproduct density of 1.42 g/ml and a metering valve of 100 μl, a dose of1000 μg could be expected through-the-valve.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention. Thus, it is intended that the present invention cover themodifications and variations of this invention provided they come withinthe scope of the appended claims and their equivalents.

1.-50. (canceled)
 51. A propellant-based dry powder composition preparedby a process comprising the steps of: (a) obtaining a dry powder of ananoparticulate drug composition, wherein the nanoparticulate drugcomposition comprises particles of a drug having an effective averageparticle size of less than or equal to about 2000 nm and a surfacemodifier adsorbed on the surface of the drug particles, wherein the drypowder of the nanoparticulate drug composition is obtained by: (i)forming an aqueous nanoparticulate dispersion of the drug and surfacemodifier; and (ii) spray-drying or freeze-drying the nanoparticulatedrug dispersion to form a dry powder of spherically shaped aggregates ofthe nanoparticulate drug and surface modifier; and (b) dispersing thedry powder in at least one propellant.
 52. The composition prepared bythe process of claim 51, wherein the aggregates have a mass medianaerodynamic diameter of less than or equal to about 100 microns.
 53. Thecomposition prepared by the process of claim 51, wherein the processfurther comprises adding a diluent to the nanoparticulate drugdispersion prior to spray-drying.
 54. The composition prepared by theprocess of claim 53, wherein the diluent is lactose or mannitol.
 55. Thecomposition prepared by the process of claim 51, wherein the processfurther comprises adding a diluent to the nanoparticulate drugdispersion prior to freeze-drying.
 56. The composition prepared by theprocess of claim 51, wherein the diluent is lactose or mannitol.
 57. Thecomposition prepared by the process of claim 51, wherein the propellantis selected from the group consisting of a chlorinated propellant, anon-chlorinated propellant, a hydrofluorinated alkane, and a halogenatedhydrocarbon propellant having a low boiling point.
 58. The compositionprepared by the process of claim 51, wherein the drug is selected fromthe group consisting of proteins, peptides, elastase inhibitors,analgesics, a drug for treating cystic-fibrosis, a drug for treatingasthma, a drug for treating emphysema, a drug for treating respiratorydistress syndrome, a drug for treating chronic bronchitis, a drug fortreating chronic obstructive pulmonary disease, a drug for treatingorgan-transplant rejection a drug for treating tuberculosis and otherinfections of the lung, antifungal drugs, a drug for treating fungalinfection, a drug for treating respiratory illness caused by acquiredimmune deficiency syndrome, an oncology drug, an anti-emetic, acardiovascular agent, beclomethasone dipropionate, naproxen,triamcinolone acetonide, budesonide, and an anti-emetic.
 59. Thecomposition prepared by the process of claim 51, wherein the surfacemodifier is selected from the group consisting of a nonionic surfactantand an ionic surfactant.
 60. The composition prepared by the process ofclaim 51, wherein the surface modifier is selected from the groupconsisting of tyloxapol, cetyl pyridinium chloride, gelatin, casein,lecithin, dextran, glycerol, gum acacia, cholesterol, tragacanth,stearic acid, benzalkonium chloride, calcium stearate, glycerolmonostearate, cetostearyl alcohol, cetomacrogol emulsifying wax,sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castoroil, polyoxyethylene sorbitan fatty acid esters; polyethylene glycols,dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidalsilicon dioxide, phosphates, sodium dodecylsulfate,carboxymethylcellulose calcium, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol,polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer withethylene oxide and formaldehyde, poloxamers, poloxamines, a chargedphospholipid, dioctylsulfosuccinate (DOSS), dialkylesters of sodiumsulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether,sulfonate, a mixture of sucrose stearate and sucrose distearate,p-isononylphenoxypoly-(glycidol), C₁₈H₃₇CH₂(CON(CH₃)—CH₂(CHOH)₄(CH₂OH)₂,decanoyl-N-methylglucamide, n-decyl β-D-glucopyranoside, n-decylβ-D-maltopyranoside, n-dodecyl β-D-glucopyranoside, n-dodecylβ-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl β-D-thioglucoside, n-hexylβ-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noylβ-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl β-D-thioglucopyranoside.
 61. Thecomposition prepared by the process of claim 51, wherein the drug has aconcentration selected from the group consisting of about 10 mg/g ormore, about 100 mg/g or more, about 200 mg/g or more, about 400 mg/g ormore, about 600 mg/g or more, and about 900 mg/g.
 62. The compositionprepared by the process of claim 51, wherein the aggregates have a massmedian aerodynamic diameter selected from the group consisting of fromabout 5 μm to about 100 μm, from about 30 μm to about 60 μm, from about2 μm to about 10 μm, from about 2 μm to about 6 μm, and about 2 μm.